Renewed interest in the hepatic injury produced by methyldopa (MD) has been stimulated by recent reports that the antihypertensive drug may initiate chronic active liver disease, occasionally with a fatal outcome. The hepatic damage has been attributed to hypersensitivity rather than to direct toxicity, but careful review of the literature reveals that the syndrome is similar to that produced by isoniazid. Most individuals fail to show constitutional features indicative of an allergic response, but usually demonstrate hepatic injury upon rechallenge only after lengthy re-exposure to MD. Moreover, MD produces mild, clinically covert, hepatic injury of 15% of recipients when liver function tests are monitored and thus the injury is not restricted to rare, idiosyncratic individuals. We have been interested in elucidating the role of the liver microsomal cytochrome P-450 system in a possible metabolic activation of MD.